Different types of cancer have been shown to involve at least in part over activation of receptor-tyrosine-kinases such as cMET, and VEGFR. Cancers include e.g. colorectal cancer, breast cancer, and pancreatic cancer.
CD44 has been discussed as having a role in e.g. HGF dependent activation of receptor-tyrosine-kinases such cMET, ERK and VEGFR (see inter alia, Ponta et al., Nature Reviews (2003), 4, 33-45 and Tremmel et al., Blood (2009), 25, 5236-5244). Further, expression of an alternatively spliced form of CD44, namely CD44v6 has been shown to occur in some of the cancers being characterized by over-activation of receptor-tyrosine-kinases. Peptides, which are able to block CD44v6 mediated activation of receptor-tyrosine-kinases have been discussed as being potentially useful in treatment of such cancers.
However, there is a continuing interest for pharmaceutically active agents that allow treatment of such cancers, such as e.g. pancreatic cancer.
In the United States, pancreatic cancer is the second most common malignant tumor of the gastrointestinal tract and the fourth leading cause of cancer-related death in adults (Cancer Stating Manual, 7th Edition, 2010, American Joint Committee on Cancer, Springer). It is a malignant neoplasm originating from transformed cells arising in tissues forming the pancreas. The most common type of pancreatic cancer is adenocarcinoma or exocrine pancreatic cancer, which are tumors exhibiting glandular architecture on light microscopy arising with the exocrine component of the pancreas. A minor type arises from pancreatic duct cells and are classified as neuroendocrine tumors.
Treatment of pancreatic cancer typically depends on the stage of the cancer. Although only localized cancer is considered suitable for surgery with curative intent at present, only about 20% of cases are diagnosed with localized disease. Surgery can also be performed for palliation, if the malignancy is invading or compressing the duodenum or colon. Further treatment options include radiation and palliative chemotherapy. At present chemotherapy includes treatment with gemcitabin or combination therapies with gemcitabin such as gemcitabin/oxaliplatin or gemcitabin/cisplatin. Despite intensive research efforts, no treatment is currently available which would be considered to provide a long-term progression-free survival. Pancreatic cancer is therefore to date one of the malignancies with the worst prognosis of all neoplasias. Particularly if metastases have spread across the body such as to the liver, the peritoneal cavity and the lungs, no efficient treatment is available, which would allow to effectively regression of existing metastases.
Similar problems exist for other cancers, which have already formed metastases. For many of these cancers, palliative chemotherapy may be the only therapeutic option.
Thus, there is a need for new compounds and methods which can be used to treat cancers such as pancreatic cancers, when metastatic spreading has occurred.